Latasopt

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LATAOPT (LATASOPT)

Composition:

Active substance: latanoprost;

1 ml of solution contains latanoprost 0.05 mg;

Excipients: sodium hydrogen phosphate, dodecahydrate; sodium dihydrogen phosphate, dihydrate; sodium chloride; benzalkonium chloride; water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: colorless clear solution.

Pharmacotherapeutic group.

Antiglaucoma agents and miotics. Prostaglandin analogues. ATC code S01E E01.

Pharmacological properties.

Pharmacodynamics.

The active ingredient of the medicinal product, latanoprost, a prostaglandin F2α analogue, is a selective agonist of the prostaglandin FP receptor, which reduces intraocular pressure (IOP) by increasing the outflow of aqueous humor. Reduction in IOP in humans begins approximately 3–4 hours after administration of latanoprost, with maximum effect observed at 8–12 hours. The hypotensive effect lasts for at least 24 hours.

Preclinical studies have shown that latanoprost is effective as monotherapy. In addition, clinical studies on the combined use of latanoprost have demonstrated that it is also effective in combination with beta-adrenergic blockers (timolol). Short-term (1 or 2 weeks) studies show that the effect of latanoprost is additive when used in combination with adrenergic agonists (dipivefrin), oral carbonic anhydrase inhibitors (acetazolamide), and at least partially additive when used with cholinergic agonists (pilocarpine).

Clinical studies have shown that latanoprost does not significantly affect the production of intraocular fluid. No effect of latanoprost on the blood-ocular barrier has been observed.

In experimental studies conducted in monkeys, latanoprost at clinically recommended doses had no significant or only minimal effect on intraocular blood flow; however, topical application of latanoprost may cause mild to moderate conjunctival and episcleral hyperemia.

Long-term use of latanoprost in monkeys that underwent extracapsular lens extraction did not affect retinal vessels as assessed by fluorescein angiography.

Latanoprost did not cause leakage of fluorescein into the posterior segment of pseudophakic human eyes during short-term treatment.

No significant pharmacological effect of latanoprost on the cardiovascular and respiratory systems has been observed at clinical doses.

Children.

The efficacy of latanoprost in pediatric patients (≤18 years of age) was demonstrated in a 12-week, double-masked, clinical trial comparing latanoprost with timolol in 107 patients diagnosed with ocular hypertension and childhood glaucoma. In this study, gestational age of neonates was at least 36 weeks. Patients received either 0.005% latanoprost once daily or 0.5% timolol (or 0.25% at the investigator’s discretion for patients under 3 years of age) twice daily. The primary efficacy endpoint was mean reduction in IOP from baseline at week 12 of the study. Mean reductions in IOP were similar between the latanoprost and timolol treatment groups. Across all age groups studied (birth to 3 years, 3 to 12 years, and 12 to 18 years), mean IOP reductions at week 12 were similar between patients receiving latanoprost and those receiving timolol. However, efficacy data for latanoprost in the age group from birth to 3 years were obtained from only 13 patients, and no significant efficacy was demonstrated in the 4 patients who represented the birth to 1 year age group in the clinical trial. Data on use in preterm neonates (born before 36 weeks of gestation) are lacking.

IOP reduction outcomes in the subgroup of patients with primary congenital glaucoma/infantile glaucoma (PCG) were similar between patients treated with latanoprost and those treated with timolol. Results in the non-PCG subgroup (i.e., patients with, for example, juvenile open-angle glaucoma, aphakic glaucoma) were similar to those in PCG patients.

The effect on IOP was evident after the first week of treatment (see table) and was maintained throughout the 12-week study period, similar to that observed in adults.

Reduction in IOP (mm Hg) at week 12 of the study according to active treatment group and initial diagnosis

SE – standard error.

†Adjusted mean based on analysis of covariance (ANCOVA) model.

Pharmacokinetics.

Absorption.

Latanoprost (molecular weight 432.58) is an isopropyl ester of the active substance, i.e., a prodrug which is inactive itself but becomes biologically active after hydrolysis to form latanoprost acid.

Prodrugs penetrate well through the cornea, and like all drugs reaching the intraocular fluid, they are hydrolyzed during passage through the cornea.

Distribution.

Studies in humans have shown that maximum concentration in the intraocular fluid is reached approximately 2 hours after topical administration. After topical administration in monkeys, latanoprost is distributed mainly in the anterior segment, conjunctiva, and eyelids. Only a negligible amount reaches the posterior segment.

Elimination.

Ocular metabolism of latanoprost acid is negligible. The main metabolism occurs in the liver. In humans, the plasma half-life is 17 minutes. The primary metabolites (1,2-dinor and 1,2,3,4-tetranor) have no or only weak biological activity and are excreted predominantly in urine.

Paediatric population.

An open-label pharmacokinetic study of plasma concentrations of latanoprost acid was conducted in adult patients and paediatric patients (from newborns up to 18 years of age) with ocular hypertension and glaucoma. Patients in all age groups received treatment with 0.005% latanoprost, one drop in each eye, for at least 2 weeks. Systemic exposure to latanoprost acid was approximately twice as high in patients aged 3 to 12 years and six times higher in children under 3 years of age compared to adult patients. However, a wide safety margin for latanoprost with regard to systemic adverse effects was maintained. The median time to reach maximum plasma concentration was 5 minutes after latanoprost dosing across all age groups. The median plasma half-life was short (less than 20 minutes) and similar in both paediatric and adult patients, resulting in no accumulation of latanoprost acid in the systemic circulation at steady state.

Clinical characteristics.

Indications.

• Reduction of elevated intraocular pressure in adult patients (including elderly patients) with open-angle glaucoma and elevated intraocular pressure.
• Reduction of elevated intraocular pressure in pediatric patients with elevated intraocular pressure and childhood glaucoma.

Contraindications.

Hypersensitivity to the active substance and/or to any of the other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Comprehensive data on the interaction of latanoprost with other medicinal products are lacking.

Paradoxical increase in IOP has been reported following concomitant ocular administration of two prostaglandin analogs. Therefore, concomitant use of two or more prostaglandins, prostaglandin analogs, or their derivatives is not recommended.

Drug interaction studies have been conducted only in adult patients.

Special precautions for use

Latanoprost may cause a gradual change in eye colour due to increased brown pigmentation of the iris. Patients should be informed about the possibility of a permanent change in eye colour before initiating treatment. Treatment of only one eye may lead to permanent heterochromia.

Colour change is observed predominantly in patients with mixed iris colour, such as blue-brown, grey-brown, yellow-brown, or green-brown. In clinical trials with latanoprost, colour change usually occurred within the first 8 months of treatment, less frequently during the second or third year, and was not observed after the fourth year of treatment. Progression of iris pigmentation decreases over time and stabilizes after 5 years. The effect of increased pigmentation after 5 years of latanoprost treatment has not been evaluated. In an open-label 5-year safety study, increased iris pigmentation was recorded in 33% of patients (see section "Adverse reactions"). Iris colour changes are mostly minor and often clinically unnoticeable. The incidence of cases in patients with mixed iris colour ranged from 7% to 85%, with the highest frequency observed in patients with yellow-brown iris colour. Eye colour changes were not observed in patients with uniformly blue eyes and were rare in patients with uniformly grey, green, or brown eyes.

The colour change occurs due to increased melanin content in the iris stromal melanocytes, not due to an increase in the number of melanocytes. Typically, brown pigmentation around the pupil spreads concentrically toward the periphery of the affected eye, although the entire iris or parts of it may become more brown. After discontinuation of treatment, further progression of brown iris pigmentation has not been observed. To date, clinical studies have not provided evidence that this phenomenon is associated with any symptoms or pathological changes.

No changes in iris nevi or freckles have been observed under the influence of treatment. In clinical studies, no pigment accumulation has been observed in the trabecular meshwork or any other part of the anterior chamber of the eye. Results from 5 years of clinical use of latanoprost indicate that increased iris pigmentation does not lead to clinical complications, and treatment may be continued in case of iris pigmentation changes. However, patients should undergo regular examinations, and if the clinical situation requires, the use of the medicinal product should be discontinued.

Experience with latanoprost use is limited in chronic angle-closure glaucoma, open-angle glaucoma in pseudophakic patients, and pigmentary glaucoma. Currently, there are no data on the use of latanoprost in inflammatory or neovascular glaucoma or in inflammatory eye diseases. Latanoprost has no or minimal effect on the pupil, but data on its use during acute attacks of angle-closure glaucoma are lacking. Therefore, the medicinal product should be used with caution in such conditions until more data become available.

Data on the use of latanoprost during the perioperative period of cataract surgery are limited. The medicinal product should be used with caution in such patients.

The medicinal product should be used with caution in patients with a history of herpetic keratitis and should be avoided in patients with active herpes simplex virus keratitis or with a history of recurrent herpetic keratitis, particularly associated with prostaglandin analogues.

Cases of macular edema have been reported (see section "Adverse reactions"), primarily in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and in patients with known risk factors for cystoid macular edema (such as diabetic retinopathy and retinal vein occlusion). The medicinal product should be used with caution in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and in patients with known risk factors for cystoid macular edema.

The medicinal product may be used with caution in patients with known risk factors for the development of iritis/uveitis.

Experience with latanoprost in patients with bronchial asthma is limited, although some cases of asthma exacerbation and/or dyspnea have been reported during the post-marketing period. Until sufficient clinical experience is accumulated, the medicinal product should be used with caution in patients with bronchial asthma (see also section "Adverse reactions").

Skin colour changes in the periorbital area have been observed, with most cases reported in patients from Japan. Current data suggest that periorbital skin pigmentation changes are not permanent and, in some cases, may resolve during continued treatment with latanoprost.

Latanoprost may gradually change the eyelashes and vellus hair around the treated eye and adjacent areas, including increased length, thickness, pigmentation, and number of eyelashes or vellus hairs, as well as misdirected eyelash growth. Changes in eyelashes are reversible and resolve after discontinuation of the medicinal product.

The medicinal product contains benzalkonium chloride, which may cause eye irritation, symptoms of dry keratoconjunctivitis, disruption of the tear film integrity, and corneal damage. In cases of frequent or prolonged use of the medicinal product, careful monitoring is recommended in patients with dry eye syndrome or corneal damage.

Benzalkonium chloride may also cause discoloration of soft contact lenses. Contact with soft contact lenses should be avoided. Patients should be advised to remove soft contact lenses before applying the eye drops and to wait at least 15 minutes before reinserting the contact lenses (see section "Dosage and administration").

Use during pregnancy or breastfeeding

Pregnancy

The safety of latanoprost use in pregnant women has not been established. Its pharmacological action poses a potential risk to pregnancy, the fetus, or the newborn. Therefore, the medicinal product should not be used during pregnancy.

Breastfeeding

Latanoprost and its metabolites may pass into breast milk; therefore, women who are breastfeeding should either discontinue the medicinal product or stop breastfeeding.

Fertility

Animal studies have shown that latanoprost has no significant effect on fertility in either males or females.

Ability to affect reaction speed when driving or operating machinery

Latanoprost has a minor influence on the ability to drive or operate machinery. As with other ophthalmic solutions, the use of the medicinal product may cause transient blurred vision. Patients should not drive or operate machinery until this effect has subsided.

Dosage and Administration.

The medicinal product is intended for topical use.

Adults (including elderly patients)

The recommended dose is 1 drop in the affected eye once daily. Optimal effect is achieved when the medicinal product is administered in the evening.

The medicinal product should not be used more frequently than once daily, as more frequent administration has been shown to reduce the effectiveness of intraocular pressure reduction.

If a dose is missed, treatment should be continued by taking the next dose at the usual time.

As with any ophthalmic drops, to reduce potential systemic absorption, it is recommended to press on the lacrimal sac in the medial canthus area (punctal occlusion) for 1 minute immediately after instillation of each drop.

Contact lenses should be removed before instilling the drops and may be reinserted 15 minutes after administration.

When using multiple topical ophthalmic agents, the products should be administered at intervals of at least 5 minutes.

Children.

The medicinal product can be used in pediatric patients at the same dosage as in adults.

Data on the efficacy and safety of the medicinal product in patients under 1 year of age are very limited (4 patients) (see section "Pharmacological Properties"). There are no available data on use in preterm infants (born before 36 weeks of gestation).

In children aged from birth to 3 years, primarily suffering from primary congenital glaucoma, surgical intervention (e.g., trabeculotomy/goniotomy) remains the primary treatment approach.

Long-term safety of latanoprost use in children has not been established.

Overdose.

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse reactions have been reported with latanoprost overdose.

The following information may be useful in case of accidental ingestion of the medicinal product. One vial contains 125 mcg of latanoprost. More than 90% of latanoprost is metabolized during first-pass liver metabolism. Intravenous infusion of latanoprost at a dose of 3 mcg/kg in healthy volunteers did not cause any symptoms; however, at doses of 5.5–10 mcg/kg, it caused nausea, abdominal pain, dizziness, increased fatigue, hot flushes, and increased sweating.

In monkeys, intravenous infusion of latanoprost at doses up to 500 mcg/kg did not show any significant effects on the cardiovascular system.

Intravenous administration of latanoprost in monkeys was associated with transient bronchospasm. However, when latanoprost was administered topically to the eye at doses 7 times higher than the clinical dose, no bronchoconstriction was observed in patients with moderate bronchial asthma.

In case of overdose, symptomatic treatment should be administered.

Adverse Reactions

Most adverse reactions are related to the eye. In an open 5-year safety study of latanoprost, iris pigmentation changes were observed in 33% of patients (see section "Special Warnings and Precautions for Use"). Other ocular adverse events are usually temporary and occur after administration.

Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

Infections and parasitic diseases:

Rare – Herpetic keratitis*§.

Nervous system disorders:

Uncommon – Headache*, dizziness*.

Eye disorders:

Very common – Increased iris pigmentation, mild to moderate conjunctival hyperemia, eye irritation (burning sensation with feeling of "sand in the eye", itching, stinging, foreign body sensation), changes in eyelashes and vellus hair of eyelids (increased length, thickness, pigmentation, and number of eyelashes);
Common – Punctate keratitis (mostly asymptomatic), blepharitis, eye pain, photophobia, conjunctivitis*;
Uncommon – Eyelid edema, dry eye, keratitis*, blurred vision, macular edema including cystoid macular edema*, uveitis*;
Rare – Iritis*, corneal edema*, corneal erosion, periorbital edema, trichiasis*, distichiasis, iris cyst*§, local skin reaction on eyelids, darkening of palpebral skin of eyelids, ocular conjunctival pseudopemphigoid*§;
Very rare – Periorbital changes and eyelid changes leading to deepening of eyelid folds.

Cardiac disorders:

Uncommon – Angina pectoris, tachycardia;
Very rare – Unstable angina*.

Respiratory, thoracic and mediastinal disorders:

Uncommon – Asthma*, dyspnea*;
Rare – Exacerbation of bronchial asthma.

Gastrointestinal disorders:

Uncommon – Nausea, vomiting.

Skin and subcutaneous tissue disorders:

Uncommon – Skin rash;
Rare – Pruritus.

Musculoskeletal and connective tissue disorders:

Uncommon – Myalgia*, arthralgia*.

General disorders and administration site conditions:

Uncommon – Chest pain*.

* Adverse reaction to latanoprost identified during the post-marketing period.
§ Frequency of latanoprost adverse reaction estimated using the "Rule of Three".

Very rare cases of corneal calcification associated with ophthalmic solutions containing phosphate have been reported in some patients with significantly damaged corneas.

Children

In two short-term clinical studies (≤12 weeks) involving 93 pediatric patients (25 and 68), the safety profile of latanoprost was similar to that observed in adults, with no new adverse events identified. Short-term safety profiles were also similar across different pediatric subgroups (see section "Pharmacological Properties"). In pediatric patients, nasopharyngitis and increased body temperature were reported more frequently than in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 3 years.

After opening the bottle, the product can be used for up to 4 weeks.

Storage conditions.

Store at 2–8°C, protected from light and kept out of reach of children. After first opening, store the bottle at a temperature not exceeding 25°C.

Packaging.

2.5 ml in a dropper bottle; 1 dropper bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

C.O. Rompharm Company S.R.L., Romania /
S.C. Rompharm Company S.R.L., Romania.

Manufacturer's address and location of business activity.

Otopeni, Eroilor Street No. 1A, 075100, Ilfov County, Romania /
Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov, Romania.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.